A Rare Case of Empagliflozin-Induced Euglycemic Diabetic Ketoacidosis Obscured by Alkalosis

Empagliflozin-induced euglycemic diabetic ketoacidosis is a life-threatening metabolic complication of diabetes mellitus characterized by metabolic acidosis, ketonemia, and relatively normal serum glucose levels. We present a rare case of empagliflozin-induced diabetic ketoacidosis obscured by alkalosis. This case report aims to create awareness among clinicians about this entity and consider this diagnosis in their differential, especially in patients taking sodium-glucose co-transporter (SGLT-2) inhibitors who present to the hospital with unspecific symptoms that may not suggest DKA.


Introduction
Empagliflozin is a sodium-glucose co-transporter inhibitor (SGLT-2i) that has been approved by the Food and Drug Administration (FDA) since August 2014 for the treatment of type II diabetes mellitus (T2DM) [1]. The primary mechanism of action of SGLT-2i is by inhibition of glucose uptake in proximal tubules, leading to glycosuria [2]. Common side effects of this drug class include increased risk of urinary tract infections, genital mycotic infections, and dehydration [3]. In May 2015, regulatory agencies issued a warning that SGLT-2i may cause diabetic ketoacidosis (DKA) with uncharacteristically mild to moderate glucose elevations [3]. DKA-associated with SGLT-2i has rates ranging from 0.16 to 0.76 events per 1,000 patientyears in patients with T2DM [4]. Empagliflozin-induced DKA usually presents with severe metabolic acidosis with elevated anion gap but only mild to moderate hyperglycemia, also known as euglycemic DKA (eDKA). Common precipitants of eDKA include infection, alcohol use, starvation, pregnancy, acute illness, and in patients who are fasting prior to surgeries without maintenance fluids containing dextrose. Appropriate treatment is often delayed as it presents with normal glucose levels in serum; hence, it is of utmost importance that physicians possess a high level of suspicion for eDKA in patients treated with SGLT-2i, especially when the initial presentation is atypical, for example, eDKA presenting with alkalosis instead of acidosis. We describe a case of empagliflozin-induced eDKA in a patient with T2DM who presented with a mixed acid-base disorder with predominant alkalosis.

Case Presentation
A 37-year-old man presented to the emergency department (ED) with a two-day history of nausea and multiple episodes of non-bilious, non-bloody vomiting. The patient had been seen two days prior complaining of similar symptoms and was treated with anti-emetics and was discharged home after symptomatic improvement. The patient denied fever, abdominal pain, and diarrhea. Past medical history was significant for T2DM treated with empagliflozin 25 mg daily for one year. The patient stated compliance with the medication, and the last dose taken was one day before admission. Vital signs on admission reported a heart rate of 97 beats per minute; respiratory rate of 20 breaths per minute, blood pressure of 164/97 mmHg, and a temperature of 98.8 o F (37.1 o C); pulse oximetry was 99% on room air. The patient appeared uncomfortable, intermittently sticking fingers down his throat while retching. Oral mucosa was dry, abdomen was soft, non-tender, non-distended. The remainder of the physical exam was unremarkable. Pertinent biochemical analysis ( Table 1) on day one of admission included: a mild increase in glucose, low carbon dioxide, elevated anion gap, serum creatinine at the upper limit of a normal, mild increase in white blood cell count, elevated lactic acid, normal blood osmolality, large ketones, and negative blood alcohol level. Urine analysis showed ketonuria and glucosuria. Initial venous blood gas (VBG) as depicted in Table 2 was remarkable by elevated pH, low partial pressure of carbon dioxide, and low bicarbonate. The patient was admitted to the general medical floor and was started on IV fluids and antiemetics. No antibiotics were prescribed.  Sodium 138  140  141  139  135  137  136  134  137  139  141  137  138   Chloride 95  102  103  104  97  101  100  103  106  107  109  101  101   Carbon   dioxide  19  17  19  15  14  14  17  13  15  19  21  23  26   Glucose 141  116  117  125  182  147  147  156  134  147  182  163  171   Anion   Gap  24  21  20  24  24  22  19  18  16  13  11 13 11  By the second day of the hospital stay, symptoms did not improve with a drop in the pH and bicarbonate ( Table 2). Endocrinology and Critical care medicine were consulted, and the patient was transferred to the intensive care unit to initiate IV Insulin infusion as per protocol and IV fluids. Subsequent VBG and basic metabolic panel showed improvement with a gradual increase in serum bicarbonate levels, and the anion gap was closed seven hours after initiation of IV insulin infusion (Tables 1, 2). The patient was transitioned to basal insulin after oral route was tolerated by the patient. Subsequently, laboratory parameters were monitored for 24 hours for DKA relapse. By the fourth day of hospitalization, the patient was discharged home, empagliflozin was discontinued, and the patient was started on Metformin 500 mg daily.

Discussion
Diabetic ketoacidosis is a life-threatening metabolic complication of DM, traditionally defined by hyperglycemia (>250 mg/dL [>13.9 mmol/L]), ketosis (increased plasma ketones), and anion-gap acidosis [5]. DKA is frequently seen in high-dependency units such as critical care units and the emergency department. eDKA is characterized by severe metabolic acidosis (pH < 7.3), bicarbonate < 18 mEq/L, and anion gap > 12 in the presence of glucose levels < 250 mg/dL with ketonemia [4]. In summary, eDKA can be defined as DKA without marked hyperglycemia.
The pathophysiologic mechanisms behind eDKA include a decrease in insulin secretion or action, a decrease in glucose uptake by the cells, increase in counterregulatory hormones such as glucagon, cortisol, and epinephrine, resulting in increased glucagon to insulin ratio, thereby favoring increased lipolysis, increase in free fatty acids and ketoacidosis. SGLT-2 is a sodium-glucose co-transporter present in the apical surface of proximal renal tubules. SGLT-2 expression is enhanced in T2DM and reabsorbs glucose and sodium. SGLT-2i act by blocking glucose's reabsorption in the proximal convoluted tubule, thereby increasing glucose excretion [6][7][8]. Ketoacidosis occurs by two central mechanisms, primarily due to the lack of insulin. First, the stimulation of free fatty acid production that travels through the bloodstream to the liver leads to ketogenesis. Furthermore, SGLT-2i stimulates glucagon secretion in pancreatic alpha cells, reducing insulin to glucagon ratio. High glucagon levels interfere with fatty acid metabolism by decreasing the production of malonyl-CoA, eventually promoting beta-oxidation and ketoacid production [9,10].
In our case, the patient presented with a triple acid-base disorder with a final alkalotic pH, obscuring the usual metabolic acidosis seen in eDKA. The metabolic acidosis was caused by ketonemia and lactic acidosis, the concomitant metabolic alkalosis (confirmed by an initial delta anion gap/delta bicarbonate of 2.4) was secondary to persistent vomiting, and the respiratory alkalosis (low pCO 2 in the setting of high pH) due to hyperventilation. Similar combined acid-base disturbances were described in studies by Kumar et al. and Svart et al. They found patients presenting with intractable vomiting and diabetic keto-alkalosis likely due to volume contraction [11,12]. DKA was not strongly suspected in our patient since serum glucose was 141 mg/dL and alkalotic pH in the VBG. After initial management with antiemetics and IV crystalloids, metabolic alkalosis resolved. However, metabolic acidosis persisted, demonstrated by decreased bicarbonate, elevated anion gap, and serum ketones. This presentation of a triple acid-base disturbance and euglycemia caused a delay in management in our patient. After starting insulin drip, the anion gap closed, and bicarbonate levels normalized, supporting our diagnosis of eDKA.
Treatment of eDKA is virtually the same as hyperglycemic DKA, consisting of aggressive hydration, insulin, and electrolytes homeostasis. The American Association of Clinical Endocrinologists and American College of Endocrinology recommend minimizing the risk of SGLT-2i associated DKA by avoiding excessive alcohol intake, minimizing starvation or decreased carbohydrate intake, and stopping SGLT-2i at least 24 hours before elective surgery [3,13]. Knowing these triggers will help us adequately prescribe SGLT-2i and withhold them in any situation that might precipitate DKA [14].

Conclusions
Given the current widespread use of empagliflozin due to its cardioprotective effects in diabetic and nondiabetic patients, the number of cases of eDKA will continue to rise and can be easily missed, especially in patients who are yet not diagnosed with diabetes. Hence, providers must keep eDKA in their differential in patients taking SGLT-2i who present to the outpatient and/or inpatient settings with unspecific symptoms such as nausea and vomiting even if they are seemingly not acidotic. Early recognition of this potential side effect can translate into prompt treatment and shorter hospital length of stay. Patients must be routinely informed of the common and uncommon side effects of empagliflozin (including eDKA) and the potential triggers to decrease the risk of complications.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.